Pathophysiology and Therapy of Pruritus in Allergic and Atopic Diseases J

REVIEW ARTICLE Pathophysiology and therapy of pruritus in allergic and atopic diseases J. Buddenkotte1 & M. Steinhoff2

1Deparment of Dermatology, Boltzmann Institute for Cell- and Immunobiology of the Skin, University Hospital Mu¨ nster, Mu¨ nster, Germany; 2Depatments of Dermatology and Surgery, University of California, San Francisco, CA, USA

To cite this article: Buddenkotte J, Steinhoff M. Pathophysiology and therapy of pruritus in allergic and atopic diseases. Allergy 2010; 65: 805–821.

Keywords Abstract atopic dermatitis; itch; nerve; Pruritus (itch) is a major characteristic and one of the most debiliating symptoms in pathophysiology; pruritus; therapy. allergic and atopic diseases and the diagnostic hallmark of atopic dermatitis. Pruri- Correspondence tus is regularly defined as an unpleasant sensation provoking the desire to scratch. Martin Steinhoff, MD, PhD, Departments of Although we achieved rather good knowledge about certain inducers of itch such as Dermatology and Surgery, University of neuropeptides, amines, l-opioids, cytokines and proteases, for example, less is California San Francisco, 513 Parnassus known about the pathophysiological specifities among the different diseases, and the Ave, Room S-1268, 94143 San Fransico, therapeutic consequences which may derive thereoff. This review dissects the role of CA, USA. mediators, receptors and itch inhibitors on peripheral nerve endings, dorsal root Tel.: +1 415 476 6978 ganglia, the spinal cord and the CNS leading to the amplification or – vice versa – Fax: +1 415 476 0936 suppression of pruritus. As the treatment of pruritus in allergic and atopic skin dis- E-mail: [email protected] ease is still not satisfactory, knowing these pathways and mechanisms may lead to novel therapeutic approaches against this frequently encountered skin symptom. DOI:10.1111/j.1398-9995.2010.01995.x

Edited by: Jean Bousquet

Based on early psychophysical studies on itch (4), it was Itch transmission by the nervous system believed that itch is nothing but a low-intensity pain. Con- The skin constitutes a barrier between ‘outside’ environment cepts from those times declared that itch is enciphered in spe- and ‘inner’ body. Therefore, one of its main tasks is to pro- cific patterns of action potentials running through ‘pain tect the organism against harmful influences from the out- fibres’ or that itch emerges from combinations of other pri- side. To fullfil this task, the skin is armed with an effective mary sensory signals. However, it is clear at this stage that communication and control system. In all layers of the skin, pruritoception is a distinct entity just as nociception is a dis- specialized sensory and efferent nerve branches appear to tinct entity (5–8). Therefore, the new concept of itch trans- form an overall dense nerval network. One main ‘outside- mission is based on an important proposition: the existence to-inside’ interaction causes sensations of itch. Pruritus is reg- of a central itch-specific neuronal pathway, in other words, it ularly defined as an unpleasant sensation provoking the envisages the existence of a sensory system for pruritoception desire to scratch (1) and constitutes an essential feature of that is distinct from the sensory system for nociception atopic dermatitis (AD) (2, 3). (Fig. 1). Pruritus can be triggered by localized, systemic, peripheral or central stimuli. To relay itch information to different cere- bric areas is the specific function of a subpopulation of the Abbreviations ACh, acetylcholine; AD, atopic dermatitis; CB, cannabinoid dense nerval network in the skin, the unmyelienated C-polymo- receptor; CGRP, calcitonin gene-related peptide; CyA, cyclosporin dal nociceptive neurons (in general being histamine-sensitive). A; GRP, gastrin-releasing peptide; GRPR, gastrin-releasing peptide The free nerve endings referred to as cutaneous terminals receptor; IL, interleukin; IFN, interferon; NGF, nerve growth factor; reside in the epidermis, papillary dermis and around skin NKR, neurokinin receptor; NPY, neuropeptide Y; NT, neurotrophin; appendages and are qualified to apprehend endogenous or PAR, protease-activated receptor; PGP, protein gene product; SP, exogenous itch causing agents through an armada of relevant substance P; TRPV1, transient receptor potential vanilloid receptors. These receptors detect their corresponding ‘itchy’ (capsaicin) receptor 1; VIP, vasoactive intestinal polypeptide. ligands and send either an electrical signal to the central

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 805 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

Allergens, house dust mite, Staphylococcus aureus, Topical / systemic drugs, dermatophytes injury

Antigen-presentation Langerhans cell Keratinocyte activation Epidermis and apoptosis cytokine, chemokine, neurotrophin, pro- Blood stanoid, opioid, vessel Immune cells protease release Hyperkeratosis (mast cells, receptor upregulation plasma extravastion T cells) oedema

Brain

Protons, kinins, IL-2, IL-8, proteases, amines, IL-31, DRG prostaglandins, leukotriens, IFN-γ ? Neuropeptides cannabinoids, endothelins, neutrophins, drugs

ACh β-endorphin proteases Peripheral nerve ending (C-fibre) e. g. GPR/GPRP pruritus / pain

PAR 2?, opioids?, NK1R?

Spinal cord

Figure 1 General neuroanatomical and neurophysiologcial path- mitted to the CNS after crossing to the contralateral side. Activa- ways activated during pruritus (pruritogenic itch). Exogenous or tion of specific areas in the CNS results in the perception of itch endogenous meditors stimulate selective subtypes of peripheral C leading to ‘discomfort’ and an acute or chronic scratch response. fibre nerve endings of primary afferent neurons in the epidermis or Additionally, the associated peripheral axon reflex may lead to the dermis. High-affinity receptors for various pruritogenic mediators release of mast cell-stimulating neuropeptides (e.g. substance P) transmit the stimulus, via not completely understood intracellular thereby amplifying pruritus via release of histamine, tryptase and signaling pathways, from the periphery to the dorsal root ganglia IL-31, for example. This figure does not consider the complex inter- (DRG), and the spinal cord. DRGs can modulate this stimulus on action between pain and itch fibres on the spinal cord level where the transcriptional and posttranscriptional level, thereby modulating GRPR, opioid receptors, NK1R (post-synaptic), PAR2 (pre-synaptic peripheral and central nerve endings. Within the spinal cord, itch primary afferents) and probably other mediators/ receptors can signals can be also modulated. From lamina 1, a selective area exert exciatatory or inhibitory influences. within the the dorsal horn of spinal cord, the signal will be trans- nervous system or trigger a direct inflammatory response by the confirmation for a direct role of the NK-1 receptor in antidromic impulse transmission. From the foregoing, it is human spinal itch transmission is still lacking. From the thala- apparent that the nature of the ligand present and the corre- mus, direct excitatory connections that consist of the anterior sponding accessory receptor determine the nerval reaction (7). cingulate cortex, the insular cortex (insula) and primary and Sensory cutaneous nerves transmit the pruritic information secondary somatosensory cortices take over (6, 9, 14–16). to dorsal root ganglions and from there it reaches the spinal Itch-specific mediators in the central nervous system are cord where it can be modulated. From the lamina I, a specific elusive and so far not known. However, recent evidence side within the dorsal horn of the spinal cord, the signal is emerged that gastrin-releasing peptide receptor (GRPR), a projected to the thalamus (6, 9). On this passage, the signal bombesin-like peptide receptor homologue that is specifically crosses to the contralateral side. Nerval structures pertinent to expressed in the lamina I of the dorsal horn, might play a the transmission of pruritic information in the spine are not crucial role in mediating itch sensations in the spinal cord clarified to date, but a subset of histamine- and GRP-sensitive and might furthermore constitute a marker for central itch- neurons probably executes this assignment (5, 7, 10). A neuro- selective neurons (10). Strikingly, selective ablation of lamina toxic destruction approach carried out in rodents supplies evi- I neurons expressing GRPR in the spinal cord of mice dence for a key role of NK-1 receptor expressing neurons in resulted in severe deficiencies in scratching responses to an the transmission of itch information in the superficial spinal amarda of pruritogenic stimuli such as histamine, compound dorsal horn (11). Notably, ablation of NK1R-positive neurons 48/80, serotonin, endothelin-1, PAR2-activating peptide and compromises chronic pain behaviours in rat (12, 13), although the anti-malaria drug chloroquine (17). The severity of this

806 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases observation is that GPRP transmits itch signals independent pruritus (18, 19). Furthermore, Williams (20) suggested that of the nature of the pruritogenic stimulus. In fact, GRPR histamine may play a role in the pathogenesis of AD because constitutes the long-sought labelled line for itch sensation in intramuscular histamine injections resulted in pruritus. Based the spinal cord. on these initial experiments, histamine has doubtlessly become the most exhaustingly investigated ‘itchy’ agonist. Over the years, elevated histamine levels in lesional and non- Cutaneous neuroreceptors and mediators: induction of lesion al skin were detected (21, 22), topographically associat- pruritus ing histamine and itch. The distinct source of skin histamine The induction of itch is accomplished by a variety of agents was attributed to mast cells and keratinocytes (23–25). Also that ineract with a multitude of receptors on free nerve end- to date, four distinct histamine receptors (H1-4R) have been ings. Over the last decade of itch research, the number of identified that histamine is capable of activating (26). At least pruritogenic agents has grown far beyond the usual suspect two of them, H1R and H2R, are present on cutaneous sen- histamine. But it is the lot of several newly reported pruritic sory nerve fibres (23, 27). Therewith, all ingredients have agents to lack appropriate recognition by the scientific com- been provided to support histamine in being an important munity, while the potency of histamine to induce itch contin- pruritogen, especially as H1R- (and less so H2R) antagonists ues to be overestimated. In the following, the main mediators have been demonstrated to reduce itch in numerous clinical of cutaneous pruritus will be introduced and briefly described trials (7, 28–30). However, re-evaluating the histamine con- (see also Table 1). tent of the skin, recent investigations could not verify increased histamine levels in all pruritic diseases indicating a selective role of various mediators among the different pruri- Histamine tic diseases (31). And while re-evaluating the potency of About 80 years ago, Lewis reported that intracutaneous histamine to induce itch, it was shown in recent studies that injection of histamine causes symptoms characteristic of neu- small doses of histamine fail to produce itch but still are suf- rogenic inflammation – redness, wheal and flare – along with ficient to produce oedema and erythema upon intracutaneous

Table 1 Mediators of itch in atopic dermatitis

Substrate Provocation of itch Mechanism

Spinal inductor of itch GRP + Binding to GRPR of the spinal cord Cutaneous inductors of itch Histamine (+) Binding to histamine receptors on sensory nerve ﬁbres Neuropeptides (e.g. substance P) + Mast cell degranulation, increased concentration in lesional skin Acetylcholine + Central sensitization?

Tryptase kallikreins, cathepsin S + Binding to PAR2 on sensory nerve fibres Cytokines: Interleukin 2 + Possible release of various mediators Interleukin 8 ) Interleukin 31 + Neurotrophin-4 + m.n.n. Eosinophils +/? Release mediators like PAF, leucotriens; histamine, proteinase liberation Platelet activating factor + Histamine liberator Leukotriens + m.n.n. (LTB4?) Cutaneous suppressors of itch Cannabinoids Interruption of itch transmission Binding to CB1 and CB2 on cutaneous sensory nerve fibres Opioid peptides Induction of itch-inhibiting neurons Binding to opioid receptors on spinal level; suppression in the skin? TRP channels (Vanilloids) Suppression of itch transmission TRPV1, TRPV3 involved in itch Direct or indirect effects on sensory nerves suppressing itch Interferon gamma Suppression of pruritus m.n.n. (IFN-c receptor on nerves?) Calcineurin inhibitors Interruption of itch transmission Downregulation of pruritic cytokines by effecting T cells Binding to TRPV1 on cutaneous sensory nerve fibres Ameliorating neuropeptide release Decreasing effects of neuropeptides on mast cells?

), no induction of itch; (+), induction of weak itch; +, clear induction of itch; m.n.n., mechanism not known.

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 807 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff injection (32–35). Although in urticaria, the itchy role of model of AD (61). But still the complex role of neuropeptides histamine is well established, yet in patients with AD, intra- in pruritic AD is in need of further decipherment. cutaneous injection and also iontophoretical application of histamine did not provoke an increase but a reduction in itch Acetylcholine sensation (36–39). Additionally, intradermal injection of substance P (SP) in AD patients, an agonist stimulating hista- Over the past years, acetylcholine (ACh) emerged to become mine release from mast cells, as well produced a reduction in part of the choir of itch elicitors. As a major neurotransmit- itch perception, which not only emphasizes the marginal capac- ter in the autonomic nervous system, ACh exerts its action ity of histamine to induce pruritus in AD (40) but also lets one via binding to muscarinic (M1–M5) and nicotinic receptors. speculate about the general capacity of histamine as a potent Cultured human keratinocytes which as well express musca- pruritogen in AD. The last cloned histamine receptors, H3R rinic receptors indeed are also targeted by ACh. In vitro, this and H4R, however, might bring histamine back into focus to agent is synthesized, released and degraded by human kerat- reclaim a relative importance as a pruritogen because both inocytes in an autocrine, paracrine and endocrine mode operate at least in mice as itch receptors (41, 42). Only recently, (62–64). It has been shown in mice that carbachol and the role of histamine H4 receptor (H4R) was investigated in a bethanechol, two muscarinic agonists, by activation of T-helper type 2 (Th2)-cell-mediated mouse skin inflammation cutaneous M3 type receptors provoked itch sensation (65). In model that mimics several features of AD (43). In this mouse humans, elevated ACh expression was found in skin samples model, H4R antagonists (e.g. the small compound JNJ of AD patients indicating a role for this agent in the neuro- 7777120) were utilized and showed strong anti-inflammatory physiology of pruritus (66). effects along with significant inhibition of pruritus sensation. In psychophysical experiments with humans, application of Their roles in humans though have to be investigated in future ACh induced pain more often than itch. This observation research. But independent of prospective insights into hista- could be explained by the capability of ACh to activate mines role in itch, it already became clear that a variety of neuronal ‘itch units’ along with a considerable amount of mediators have to be involved in this process. nonitch receptors which suppress the itch sensation and pain is perceived (67). In contrast, intradermal injection of ACh in lesional AD skin evoked pruritus instead of pain (38, 68, 69). Neuropeptides It is thought that this itch-induction is obtained by a cholin- Several observations support that neuropeptides provoke itch ergic mechanism, independent of histamine. But then a cen- in human skin upon intradermal injection. For example, SP, tral sensitization for itch in patients with AD was recently a neuropeptide causing the characteristic trias of symptoms discovered (70, 71) giving an alternative explanation at hand: of neurogenic inflammation (wheal, flare, oedema), further injection of ACh along with a painful stimulus and the con- provoked itch after its intradermal injection. The itchy action version of the pain sensation into a pruritic sensation on the of SP was inhibited by antihistamines and compound 48/80 spinal level could cause the itch sensation. which clearly demonstrated an involvement of mast cell degranulation and concomitant release of mast cell mediators Tryptase in this process (42). Vasoactive intestinal peptide (VIP), somatostatin, secretin and neurotensin seem to utilize this Stimulation of mast cells and keratinocytes not only release same pathway (42, 44–47). The concept for the pathophysiol- histamine but also tryptase, an agent that has a long history ogy of itching caused by these neuropeptides is believed to for being suspicious of accomplishing pruritogenic actions rest upon their imbalanced cutaneous expression (48–50). (72). In 1988, it was shown that intradermal administration of This imbalance can be reflected by morphological alterations this agent into rabbit skin produced vasodilatation, erythema as in patients with allergic or AD alterations in the nerve and pruritus (73). The complex mechanism that is subject to fibre containing neuropeptide profile account for the imbal- this phenomenon was decoded in parts only recently. An ance. In this case, somatostatin-immunoreactive nerve fibres important observation for this clarification was that periph- were decreased in AD patients, for example (51), whereas on eral sensory nerve endings express a broad variety of receptors the other hand, nerve fibres positive for neuropeptide Y that are involved in inflammation. Simultaneously, it has been (NPY) were increased (51–53). Accordingly, while the tissue known for decades that acute or chronic skin inflammation concentrations of VIP were decreased, the SP concentration lowered the threshold for pruritic stimuli, and thus caused was increased in lesional skin (54–56). However, the SP- peripheral itch sensitization (71, 74). One of the key receptors induced itch responses are eventually mediated in mice by in neurogenic inflammation is the proteinase-activated recep- direct neurokinin receptor 1 (NK1R) activation, pointing at a tor 2 (PAR2). Upon demonstration that tryptase activated direct effect of SP in mediating pruritus in vivo (57–59). The PAR2 and that by this mechanism cellular effects were NK1R activation occurs via direct binding of histamine to mediated which triggered the hallmarks of neurogenic inflam- the receptor expressed on the surface of mast cells (60). Com- mation oedema, plasma extravasation and recruitment of pounds inhibiting the docking to or, in general, the activation leucocytes (75), PAR2 aroused the suspicion of being an ‘itchy of NK1R should therefore posses the capability to alleviate receptor’. This thesis was then further nurtured by a more itch sensation. Accordingly, the NK1R antagonist BIIF 1149 recent study where not only an enhanced expression of both

CL effectively decreased scratching behaviour in a mouse tryptase and PAR2, on sensory nerves during AD was

808 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases detected but also the triggering of itching in AD patients by (TRPM), the polycystin (TRPP), the ankyrin transmembrane

PAR2 agonists was demonstrated (76). It is not clear to date protein 1 (TRPA), the mucolipin (TRPML) and the vanilloid whether the remaining PAR family members, foremost PAR1 (TRPV) subfamilies. All members of this superfamily act as and PAR4, are also involved in the itch pathway, and under nonselective calcium-permeable sensory transduction channels which circumstances proteases may induce pain, inflammation (82). Endovanilloids constitute a group of itch mediators to or pruritus in patients suffering from AD. which heterogenous agents such as eicosanoids, histamine, bradykinin, ATP and various neurotrophins (NTs) (83–86) belong where all agents share endovanilloid functions (87). Mrgpr These agents either directly and/or indirectly activate/sensitize Several G protein-coupled receptors have been shown to act TRPV1 (84, 88, 89). as key receptors in generating itch including histamine recep- Originally, TRPV1 was found to be expressed by nociceptors and PARs. This group has been extended by the work of tive sensory neurons (89) as an integrator of different pain- Liu et al. (77): Mrgprs (also termed Mrg/SNSR) are orphan inducing stimuli. Its most well-known activator is capsaicin, receptors grouped into several subfamilies (MrgprA1–A22, the pungent ingredient of hot chili peppers. Administration MrgprB1–B13, MrgprC1–C14 and MrgprD–G). Mouse gen- of this compound excites (88) but then desensitize sensory ome analysis revealed an existence of more than 50 members afferents via TRPV1 activation, a mechanism that is utilized distributed to these subfamilies. The function of Mrgprs to alleviate pain and itch in numerous skin diseases (88, in vivo was so far an enigma but it was known that the expres- 90–92). More precisely, vanilloid administration leads to a sion of MrgprAs, MrgprB4, MrgprB5, MrgprC11, and depletion of neuropeptides in the C-fibres, which disrupts the MrgprD, is restricted to subsets of small-diameter sensory communication between mast cells and skin sensory neurons neurons in DRG and trigeminal ganglia (78, 79). To unveil (91–93). Interestingly, also the calcineurin inhibitors tacroli- the Mrgpr function, targetet deletion of an Mrgpr gene cluster mus (94) and pimecrolimus (95) bind to TRPV1 suggesting a located on mouse chromosome 7 was performed. Mrgpr-clus- mode of action for these clinically important compounds. ) ) terD / mice were then challenged with pruritogenic agents. Only recently, functional TRPV1 channels were reported Histamine and compound 48/80 induced itch behaviour in on numerous nonneuronal cell types (96–98), including ) ) Wildtype mice and Mrgpr-clusterD / mice of similar intensity. human epidermal and hair follicle keratinocytes, endothelial Strikingly, chloroquine, an anti-malaria drug that is known cells, dermal mast cells and dendritic cells (99–102). TRPV1 for pruritic side-effects, elicited itch in wildtype mice only activation resulted in the release of pruritogenic cytokine (77). The group could show that the essential receptor to mediators from several of these nonneuronal cells. In kerati- mediate the itchy action of chloroquine is MrgrpA3 and that nocyte, TRPV1 was furthermore reported to mediate prolifer- chloroquine-sensitive neurons (3–4% of total DRG neurons) ation, differentiation and apoptosis, respectively (103, 104) also respond to histamine and capsaicin. Interestingly, the but recent results utilizing a functional approach with both human Mrgpr family member MrgprX1 shares a similar systemic and local resiniferatoxin (RTX) treatment question expression pattern with mouse MrgrpA3 (80) and also a functional expression of TRPV1 in primary human responds to chloroquine treatment indicating a role for this keratinocyte (105). It will be a subject of further detailed receptor in nonhistaminergic itch transmission in humans. But research to show whether endovanilloid itch mediators, still it will be interesting to see how these findings translate to besides acting on their cognate receptors, activate/sensitize the human situation: chloroquine induced itch is common TRPV1 expressed on itch-mediating sensory neurons only or among black Africans but less common among other races also address TRPV1 expressed on other skin cells since the (81). Still there is no doubt that the putative itchy action of specificity of current antibodies against TRPV1 are question- MrgprX1 and its importance in the pathophysiology of pru- able. In other words, topically applied capsaicin may not ritic diseases such as AD will be investigated soon. Alongside, only desensitize TRPV1-mediated signalling in neuronal cells it is tempting to speculate which endogenous agonist(s) acti- but may also provoke same in the many other skin cells to vate this subset of MrgprX1-positive primary sensory fibres in counteract a pruritogenic outcome. the skin and whether an imbalance of its/their expression Next to TRPV1, itching sensitization might also be related might affect the outcome of chronic pruritus. Certainly the to the activation of other TRPs expressed in the skin, sensory discovery of Liu et al. may establish the ground for novel fibres and keratinocytes including TRPV2, TRPV3, TRPV4, anti-itch drugs targeted against itch-selective neurons. TRPA1 and TRPM8 (106) (Fig. 2). In fact, an important role for TRPV3 in pruritus has been shown recently. Asakawa and colleagues discovered an amino-acid substitution Cutaneous neuroreceptors and mediators: suppresion (G573S) in TRPV3 that led to an increase in ion channel of pruritus activity in keratinocytes which caused a spontaneous allergic and pruritic dermatitis in mice (107). Endovanilloids and the TRPV ion channel family Endovanilloids interact with TRPV1, an ion channel that Cannabinoids belongs to the superfamily of transient receptor potential (TRP) channels. To date, six groups of molecules complete Another suspect in the itch department is the cannabinoid this superfamily: the canonical (TRPC), the melastatin system. Cannabinoid receptor-1 (CB1) is co-localized with

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 809 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

Stimuli: Cold, heat, chemical agonists, irritants, mechanical stress (geralding) ?, allergens (indirect) ?

Human: + Na + TRPV1 Na Human: TRPV3 ? 2- Ca Ca2+ TRPV1, TRPV2 ?, TRPV 4 ? TRPV3, TRPV4 ?, Human epidermis: TRPA1 ? TRPM8 ?, TRPA1 ? TRPV1 TRPV3 TRPV4 ? Fibre TRPA1 terminal

Ca2+ Ca V Keratinocyte

Dorsal root ganglion To spinal AP cord

Figure 2 Potential role of transient receptor potential (TRP) chan- Physical as well as chemical stimuli can directly activate TRP channels mediating pruritogenic stimuli in the skin. Thermal, chemical nels on free sensory nerve endings thereby causing depolarization and mechanical stimuli can stimulate sensory nerve endings and/or of these fibres and the generation of specific action potentials (right keratinocytes via TRP channels. Free sensory nerve endings are panel). TRPV1, TRPV3, TRPV4 and TRPA1 are expressed in human located in the skin (left) and are transmit pruritic and/or painful keratinocytes, from which signals (which are not well characterized stimuli via the dorsal root sensory ganglia and the spinal cord for as of yet) are transduced to the DRG neurons (modified from further information processing to the contralateral side of the CNS. Ref. 260).

TRPV1 in sensory neurons (108) and cannabinoids interact In experimental settings, this painful stimulus can be mim- with the TRPV1-signalling pathway. This interaction triggers icked by various painful thermal, mechanical and chemical a switch of their neuronal effect from inhibition (109) to exci- stimuli (115). For instance, it is well demonstrated that electri- tation and sensitization (110) under inflammatory conditions. cal stimuli can reduce an itch sensation for hours (116). The In fact, a topically applied synthetic cannabinoid, HU210, potency of itch-inhibition though appears to be dependent on suppressed histamine-induced pruritus and reduced axon the nature of the applied stimulus: noxious heat stimuli and reflex erythema (111). CB1 as well as CB2 were also found to scratching produce a stronger itch inhibition than noxious be expressed in nonneuronal cells of the skin such as mast cold stimuli (117). Conversely, it is imaginable that analgesia cells (112, 113). In consequence, cannabinoid receptors may may reduce the competence of pain to inhibit itch whereby be involved in the neuronal–nonneuronal cellular network of pruritic sensation is amplified (118). This phenomenon is pruritogenic stimuli arising in/from skin. In addition, these observed when l-opioid receptor agonists are spinally admin- findings support an antipruritic role of the cannabinoid sys- istered as segmental pruritus arouses along with the desired tem which could be exploited for new therapy approaches in segmental analgesia (119–125). Accordingly, opioid receptor itch-accompanied skin diseases. In fact, preliminary studies antagonists may have antipruritic effects in pruritic diseases with a cannabinoid (palmitoylethanolamin) containing cream (126–132). The pruritic l-opioid receptor is expressed by assign anti-inflammtory and antipruritic properties to this C-fibres. During pain perception, l-opioid receptor antago- compound in AD (114). A very appealing consideration for nists such as naxolone are not ideal antipuritics because such administration of cannabinoid in itch therapy is the possibil- compounds can reverse opioid analgesia concurrently (133, ity of co-administration with a TRPV1 agonist. Thereby, the 134). However, a combination of high-dose intrathecal opioids patient would benefit from (i) the antipruritic impact of both with postoperative intravenous naloxone provided excellent agents and (ii) the mitigative effect of the cannabinoid on an analgesia with minor pruritic side-effects (135). acute burning sensation that is elicited by exclusive capsaicin The antipruritic j-opioid receptor (KOR), expressed by administration. Ad-fibres, seems to be a more promising target to ameliorate itching after spinal analgesia administration without engaging in the desired antinociception (136). When treated chronically Opioids with U-50488H, a selective KOR agonist, treated monkeys It is a common habit to counteract itch by scratching. To be displayed an excessive scratching activity upon agonist- more precise, itch is counteracted only by a painful stimulus. withdrawal (137) indicating an antipruritic role of KOR

810 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases when holding in mind that many withdrawal symptoms from 154) of AD patients. In addition, these findings indicate a opioids appear to be opposite to the acute effects of the role for IL-8 in the generation of pruritus but so far no study administered agonist (138, 139). In another pharmacological provided direct evidence for this thesis. Future research has monkey study, KOR agonists prevented/reversed intrathecal to clarify the connection of IL-8 and ‘itchy outcome’. A morphine-induced itch/scratching responses without interfer- novel T-cell-derived cytokine was reported to induce severe ing with intrathecal morphine analgesia (140). This outcome pruritus and dermatitis in transgenic mice: IL-31. Its targeted led to a clinical trial of a new KOR agonist, nalfurafine receptor to initiate itch was shown to consist of a heterdimer- (TRK-820), in hemodialysis patients suffering from uraemic ic receptor composition of IL-31 receptor and oncostatin pruritus resulting in a successfull amelioration of the itch sen- receptor (155) and to cause pro-inflammatory effects of acti- sation in these patients indicating an important therapeutical vated human monocytes and macrophages which may have potential of KOR agonists as antipruritic agents (141). implications for cutaneous inflammation in eczema (156). In patients with pruritic AD, the itchy pathogenesis of the Subsequent to this initial study, IL-31 was also found to be disease might in parts be ascribed to the involvement of overexpressed in pruritic atopic skin (157). Especially in opioids because b-endorphin serum levels were found to patients with prurigo nodularis, one of the most pruritic be markedly elevated (142). forms of chronic skin inflammation, IL-31 levels were To date, not much is known about a participation of opi- severely upregulated. Also a role for IL-31 in the pruritus of oid-receptors in the neuronal–nonneuronal cellular network atopiform dermatitis is under consideration (158). In vivo, of pruritogenic stimuli. It has been speculated though that staphylococcal superantigen rapidly induced IL-31 expression downregulated epidermal l-opiate receptor of AD patients in atopic individuals indicating a new link among staphylo- increases the pool of available opioid ligands, which then in coccal colonization, subsequent T-cell recruitment/activation turn induce histamine-unrelated chronic pruritus (143, 144). and pruritus induction in patients with AD.

Cytokines and inflammatory cells Interferon gamma (IFN-c) Under inflammatory conditions, cytokines are, among numer- While long-term treatment with IFN-b appears to cause ous other factors, released from cutaneous and immune cells. pruritic side-effects (159), IFN-a seems to have a beneficial Some of these cytokines are well capable of triggering pruritic effect on pruritus in various diseases (160–162). In patients sensations and release of neuropeptides from sensory nerves. suffering from AD, IFN-c treatment effectively relieved pruri- In the following, such cytokines will be briefly described. tus (163). This relief was reported by AD patients to still exist after long-term treatment with IFN-c (164). The distinct mechanism of action for IFN-c to modulate pruritus, how- Interleukins ever, has still to be identified. It is likely that the diminished Although the contribution of many interleukins in atopic and IFN-c production in peripheral blood mononuclear cells of allergic diseases is well established, the precise role of these AD patients (165) accounts for the pruritus phenomenon. immune mediators in pruritus is still unclear. For instance, a pleithropic inhibition of cytokine production achieved by Neurotrophin-4 usage of cyclosporine A resulted in the mitigation of itch in patients suffering from AD (145, 146). Also, upon prick test- Recent studies suggest a contribution of NT-4 to inflamma- ing, supernatants of mitogen-stimulated leucocytes were pru- tory and itch responses of patients with AD. NT-4 is ritic in AD patients but not in controls (147). Cyclosporin A produced by keratinocyte and highly expressed under inflam- (CyA), among other interleukins, effectively blocks the pro- matory conditions and acts growth-promoting on nerve cells. duction of IL-2. Gaspari and co-workers showed that actu- Accordingly, NT-4 expression was found to be significantly ally this distinct interleukin is a potent activator of pruritus. increased in lesional skin of patients with AD and in prurigo In their study, all cancer patients treated with IL-2 developed lesions of AD skin (166). Interestingly, IFN-c, itself a potent macular erythema with burning sensation and cutaneous pru- anti-pruritic agent, can initiate NT-4 production. These find- ritus (147). In AD patients, as well as in healthy individuals, ings suggest a close link between immune and neurotrophic a single intracutaneous injection of IL-2 resulted in a low- factors in the development of pruritus in AD. intensity intermittent local itch perception (148, 149). It has been demonstarated that bradykinin is involved in the mech- Eosinophils and basophils anism to modulate the intensity of IL-2-induced pruritus on sensory nerves (150) but the mechanism for the induction of The role of eosinophils in the pathogenesis of AD is well itch by IL-2 itself remains to be uncovered. Because the pru- established but how they engage in the pathophysiology of ritogenic response initiated by IL-2 administration is faster in pruritus during AD is still unclear. It is likely that factors AD patients than in healthy individuals, an indirect mecha- released by eosinophils such as prostanoids, kinins, cytokines, nism of action via other mediators is likely. Recently, a role leucotrienes, platelet-activating factor and proteases adopt for IL-8 in the pathogenesis of pruritus was postulated. the pruritogenic effect of eosinophils on a molecular level Enhanced level of this chemokine was detected in lesional (167–172). But it is also imaginable that the itch reponse is skin (151), plasma (152) and blood mononuclear cells (153, elicited indirectly by activation of mast cells which in turn

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 811 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff trigger the release of histamine or proteinases from eosinoph- Scratching ils. In summary, although some reports are in favour for a role of eosinophils during pruritus in various diseases (167, It is a recurring debate whether scratching itselfs precedes the 170, 172), direct evidence for a role of eosinophils for itch induction of AD or if itch and scratching are a consequence responses during AD is still lacking. Peripheral blood ba- of the presence of eczemas. The final answer to this debate is sophils are inconspicuous in patients suffering from AD. indeed not found so far, in particular the itch–scratch order However, in vitro analysis of basophil function demonstrated crucial for the pathophysiology of AD remains to be an faster histamine releasability upon stimulation (173, 174). enigma. However, results obtained from an animal study These in vitro results could not be confirmed in patients with were in favour of scratching behaviour anteceding and AD, though (175). The contribution of basophils to the thereby contributing to the development of dermatitis (188). development of itch and erythema in patients with AD is still This AD mouse model investigated the development of spon- in need of detailed investigation. taneous dermatitis by comparison of mice neonatally treated with capsaicin (Cap-NC mice) to ablate capsaicin-sensetive sensory nerves or vehicle. In the treated mice, scratching Platelet-activating factor behaviour was hardly observed and the development of der- The lipid mediator Platelet-activating factor is a component of matitis determined by elevation of the serum IgE level and several inflammatory cells such as mast cells and granulocytes the numbers of infiltrating eosinophils and mast cells was sig- with proinflammatory activity (176). One of its actions upon nificantly suppressed. Also the capability of spleen T cells to intradermal injection is to increase vascular permeability and produce both T-helper Th1 (IFN-c) and Th2 (IL-5, IL-13) thereby to cause a wheal and flare reaction along with pruri- cytokines appeared to be constrained in Cap-NC mice, indi- tus. The underlying mechanism debated is based on an indirect cating a direct correlation of scratching and subsequent pruritogenic effect via histamine release (177). Platelet-acti- immunological responses. Clinically, the prevention of itch vating factor antagonists have proved, in a double-blind study, sensation and/or itch-associated scratching behaviour may be to be able to reduce pruritus in AD patients when applied an additional important step in the treatment of AD. topically already within the initial weeks of treatment (178). Epidermal barrier Leukotriens Xerosis is a common problem of the skin of patients suffering Leukotriens are mediators with proinflammatory properties from AD. It constitutes a keratinization disorder that reflects generated from arachidonic acid, an essential fatty acid found a dysfunctional epidermal barrier. This dysfunction results in in the membrane of all cells (179). A synthesis pathway an increased transepidermal water loss and a decreased ability whose key enzyme is 5-lipoxygenase provides all known leu- of the stratum corneum to bind water (189) which may be due kotriens. Their cellular origin is reflected by 5-lipoxygenase to incomplete arrangement of intercellular lipid lamellae in expression and essentially restricted to various myeloid cells the stratum corneum (190, 191). It is well-established knowl- such as neutrophils, monocytes/macrophages, B lymphocztes edge that a disturbed epidermal barrier constitutes an activa- and mast cells. Leukotriens bind to three receptor subtypes: tor of pruritus. In fact, scratching behaviour and induction of

BLT, CysLT1 or CysLT2. pruritus are triggered by water content below 10% (192). The The contribution of leukotriens to the pathophysiology of precise mechanisms for the pruritogenic effect of a disturbed inflammatory diseases, in particular asthma, is well established epidermal barrier remain unknown. One possibility may be whereas their role in the pathogenesis of pruritus is still sub- that an impaired skin barrier simplifies the penetration of irri- ject of debate. However, intradermally injected leukotriene B4 tants and itchy agents (193, 194). Animal studies demon- was demonstrated to provoke scratching in mice (180) and strated that the epidermal barrier homeostasis and stratum high urinary leukotriene E4 levels could be correlated to noc- corneum integrity is furthermore affected by psychoemotional turnal itch (181). An increased abundance of leukotriens could stress: decrease of lamellar bodies’ formation and secretion therefore account for itch induction in AD. In fact, inhibition along with decrease corneodesmosomes production was of leukotrien receptor by zafirlukast and zileuton resulted in a observed (195). These findings suggested a correlation between reduction of pruritus in patients with AD (182–184). stress factors and decreased barrier function and might be of relevance for patients with AD (see Stress section). Trigger factors aggravating pruritus perception in atopic dermatitis Stress The skin of AD patients reveals a higher tendency to itch It has long been appreciated that both acute stress and upon minimal provocation because of reduced itch threshold chronic psychoemotional stress can trigger or modulate pruri- and prolonged itch duration to pruritic stimuli as compared tus (196–203). with healthy skin (185–187). A series of pruritus triggering To understand this correlation requires a deeper under- factors are known (186), which release mast cell mediators or standing of the neuroendocrinology and neuroimmunology vasomotor and sweat reactions to cause itch, and all may be of stress responses. Stress responses are learned, involve subjected to emotional influences (185). the cortical centres but can be reprogrammed by behavioural

812 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases and neuropharmacological/neurendocrine therapy. In patients Exogenous factors with AD, a close relationship between psychological factors, pruritus and scratching has been shown (198, 199, 204–206) Pruritus elicited by direct contact with wool in patients with – intriguing 81% of AD patients attribute emotional stress AD is a characteristic and reproducible phenomenon (217, to aggravate their pruritus (46). In turn, an experience of 218). It is likely that the irritation is caused by the spiky increased itch upon stressful events might lead to conditioned nature of wool fibres itself. Mechanical vibration seems to be itch in AD patients, which thereby could give way to a irrelevant for induction of itch because it inhibits experimen- vicious circle of aggravation and perpetuation of stress- tal, histamine-induced itch (219). Interestingly, thicker wool induced itch. Relaxation therapies that are also operant for fibres were found to provoke more intense itching than thin- pain patients like autogenic training or hypnosis have been ner fibres (220). Other irritants like lipid solvents, disinfec- found to ameliorate itch and eczema in AD patients by dis- tants (221) may additionally contribute to aggravate xerosis. tinctly treating mental stress factors (207, 208). The mecha- Contact- and aero-allergens as dust mites or pollens (212) nism of stress-induced pruritus in AD patients is not may also provoke pruritus. Microbiological agents like bacte- unravelled as of yet but an activation of the psycho-neuroen- ria (Staphylococcus aureus) or yeast may exacerbate both docrine system seems likely (198, 199). For instance, immobi- dermatitis and pruritus (186, 212). lization stress applied to rats resulted in mast cell Pruritus and erythema may be also triggered by exogenous degranulation (209) supporting the thesis that stress tension substances like proteinases from bacteria and dermatophytes may lead to increased release of pruritogenic mediators from increasing blood flow, conduct vasodilatation or release hista- mast cells in AD patients which further may results in inten- mine. Among those, heat, hot and spicy foods, hot drinks sified scratching behaviour and subsequent skin lesions (199). and alcohol are most likely to generate itch in AD patients In another study, AD patients undergoing a stress test (186, 212, 222). In early childhood, food allergies exacerbate revealed a responsive increase of IgE, blood eosinophils, eczematous skin lesions, but these food allergies mostly IFN-c and IL-4 (210). Pruritus intensity may be modulated resolve during ageing in older children and adults (222). by vasodilators responses and increased skin temperature in consequence to emotional stress (185, 211). Management of pruritus in allergic and atopic skin diseases Sweating The handling and treatment of severe itch is one of the major Generalized itching evoked by any stimulus to sweating challenges in the management of patients with allergic and (thermal, emotional stimuli) is a typical hallmark and repre- AD (Table 2). Concerning a successful suppression of pruritus, sents the most common trigger factor of itch in patients several levels have to be considered. First of all, identification with AD (185, 212, 213). Increased sweating was observed and elimination of individual trigger factors must be appreci- in lichenified skin of patients with AD. Causative factor ated as the primary goal of the management (200, 223). As might be a lowered threshold for sweat stimulation in chron- patients frequently develop some harmful self-treatments, e.g. ically pruritic and altered skin (214). The exact mechanism alcohol-containing solutions, these misconceived therapies underlying sweat-induced pruritus is far from being resolved, must be eliminated. Lotions and creams lubricating the skin but recent evidence points to a role of ACh. ACh-induced have to be recommended. To combat skin dryness, applica- eccrine sweating (215), is found to be increased in the skin tion of hydrophilic emollients and bathing with oily bath of AD patients (64), and finally acts as a sensitizer or pruri- additives is additionally helpful (223). Lipid based repair for- togenic in AD patients (68). mulations based on ceramide-dominant contents have been described to be superior in reduction of disease severity (224– 226). Adding substances such as urea, menthol, camphor and Microcirculation polidocanol to these cremas leads to an immediate short-term Clinically, itching is mostly associated with erythema and interruption of the itch. These creams can be applied by the hyperthermia. A variety of mediators for itching such as patients each time the itch starts to worsen (227). Unspecific histamine, tryptase, ACh, SP, prostaglandins are potent physical modalities are described to be beneficial like vasodilatators, rarely vasoconstrictors (NPY or catecholam- acupuncture (228) and cutaneous field stimulation (116). ines). Neuropeptide-induced itching does not vary between Another level of therapy is the handling of the scratch atopic and nonatopic patients, whereas vascular responses artefacts. Chronic pruritus induces chronic scratching or obviously show a significant difference between these two rubbing. Accordingly, erosions, ulcerations, bleding, crusts, groups. Moreover, patients with AD were more susceptible to lichenifications up to prurigo nodularis may develop. Stage- stress and showed increased vasodilatation as compared with dependent, disinfections, antimicrobials and topical corticos- controls (216). Pruritic mediators which also acts as potent teroids have to be applied. In patients with prurigo nodularis vasodilatators may be histamine and tryptase. Certain prosta- or lichen simplex associated to AD, frequently an automatic noids are effective sensitizers and vasodilatators. In sum, which scratching behaviour develops. These patients additionally receptors are the most important ones to regulate itch and need education to control scratch behaviour (229). For exam- vasodilatation among the different pruritic diseases is still a ple, the behaviour method ‘habit reversal’ can be employed matter of debate. (230). First, patients become aware of their scratching behav-

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 813 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

Table 2 Therapeutic strategies alleviating pruritus in atopic dermatitis

Therapeutical modalities Examples

Elimination of trigger factors Perspiration, xerosis, emotional stress, scratching, wearing wool fibres, using of mild soaps, detergents, hot, spicy food, hot drinks, alcoholics Skin barrier protection and restauration, itch control Emollients Bathing with oily additives Lotions, creams or sprays containing menthol, local anaesthetics, camphor, polidocanol, urea, pimecrolimus, cooling Skin care to reduce sweating-induced itch Therapy of scratch artefacts Desinfection, antibiotics, topical steroids, pimecrolimus, tacrolimus, doxepin cream 5%, amitryptiline 4% / ketamine 2% cream Interruption of itch-scratch-cycle: behaviour therapy against scraching Physical exercise Acupuncture, hypnosis Cutaneous field stimulation Symptomatic therapy: anti-inflammatory therapy Corticosteroids, topical and systemical Cyclosporin A Tacrolimus, pimecrolimus (Interferon gamma) Immunoglobulin therapy Ultraviolet irradiation (UVA1, UVA/UVB) Symptomatic therapy: interfering with l-Opioid antagonists, j-opioid agonist pathophysiology of pruritus in AD Capsaicin Cannabinoid agonists combination of high-dose antihistamines (neurokinin-1 receptor antagonist) Contradictory results Antihistamines, leukotriene antagonists Doxepin (potential: contact allergy upon long-term application) Mycophenolat mofetil Systemic therapy Gabapentin, pregabalin iour by counting scratch movements. In a second step, they focally reduce itch (38). However, an evidence-based review learn a new behaviour by reacting to scratch impulses. concerning the efficacy of antihistamines in relieving pruritus Scratch-induced skin damage caused by nocturnal scratch in AD concluded that little objective evidence exists for movements may be improved by using cotton gloves. Also H1-antihistamines to demonstrate improvement of pruritus controlled physical exercise like gymnastics or ball games (33). Topical application of the tricyclic antidepressant were demonstrated in a controlled study to teach patients to doxepin suggested to have antipruritic effects because of its high cope better with itch attacks (231). affinity to H1 histamine receptors. In fact, 5% doxepin cream As chronic scratching represents also a trigger factor and revealed improvement of histamine-induced and SP-mediated maintains the itch-scratch-cycle, the most important step in cutaneous responses but also evoked sedative effects in some the management of the AD patients is the interruption of patients (238, 239). Unfortunately, doxepin was accompanied itch by an effective symptomatical topical and/or systemical by contact allergies after long-term application (240). therapy. In general, anti-inflammatory, immunomodulating therapies as regularly applied in AD often result also in cessation of pruritus, because they suppress the inflammatory mecha- Symptomatical topical and systemical therapy nisms underlying the induction of itch. So far, most effective Studies concerning the pathophysiology of pruritus clearly and consistent antipruritics remain systemic immunomodula- demonstrated that different nociceptive mechanisms are tors such as glucocorticoids, CyA, tacrolimus, pimecrolimus involved in AD. Thus, conventional therapeutic modalities and ultraviolet radiation therapy (146, 241–244). Moreover, like antihistamines often fail to ameliorate pruritus in AD there are no evident and efficient alternatives to topical appli- (33). This is comprehensive with the idea that histamine is cation of corticosteroids or calcineurin inhibitors for the con- not the major mediator of pruritus in AD (35). Placebo- trol of acute episodes in AD (244–246). With reduction of controlled studies concerning the antipruritic effect of oral skin lesions, a decreased itch intensity results probably antihistamines have shown conflicting results in AD. In some because of reduction of inflammatory cells and protection of studies, no superior effect was observed as compared with depolarization of nerve fibres mediated directly by the steroid placebo (232–234) whereas others showed a significant anti- (247). However, treatment of a patient suffering from amyloi- pruritic effect (38, 235–237). In recent experimental studies, dosus lichen (LA) associated with AD by a combination of the H1-antihistamine cetirizine could be demonstrated to narrowband ultraviolet B phototherapy, topical corticoster-

814 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases oids and an oral antihistamine led to an improvement of AD ticability in further controlled studies. In conclusion, the as well as LA symptoms (248). Cyclosporin A, a cyclic poly- pathopysiology of pruritus in AD has not been evaluated peptide with potent immunosuppressive effects, has been completely. Accordingly, no specific antipruritic agent has reported to have a considerable itch-reliving effect in various been developed and management of itch in AD is confined to diseases including AD. In a randomised study, CyA was mainly immunomodulating therapies. However, the consider- demonstrated to significantly reduce itch intensity (146). ation of several levels may improve this distressing situation After discontinuation of this therapy, pruritus recurred for the patients. Further investigations are necessary to estab- immediately. As oral CyA has demonstrated to be effective lish antipruritic substances influencing the centrally and in AD, a topical CyA formulation has been developed to peripherally altered itch perception to interfere with the com- avoid systemic adverse effects. However, no significant plex pathophysiology of pruritus in AD. improvement of AD was found upon clinical application (249). Conclusion and perspectives Recently, much interest has been drawn to tacrolimus and pimecrolimus, both effective immunomodulators and calcineu- Amelioration of pruritus is a major goal in the treatment of rin inhibitors. Although the mode of action is similar to that patients suffering from allergic and atopic skin diseases. of CyA, the molecular weight is lower and its potency of Identification of a single effective pharmacological treatment inhibiting T-cell activation is higher. Multiple, large rando- is an old continuing demand of physicians handling and mised studies of the last years confirmed topical administra- managing itch symptoms for this disease. Promising new tion of tacrolimus and pimecrolimus to interrupt acute approaches have been made, but recent insight into the ori- attacks of AD, reduce fastly pruritus and prevent exacerba- gin and onset of pruritus leads to the conclusion that the tion after cessation of eczemas in adults and even children single treatment/compound that universally combats the itch with AD (250–253). This beneficial effect of pimecrolimus is symptom in AD patients may not be found in the near also detected in children suffering from Netherton syndrome future. Because itch pathophysiology is too complex involv- (254). Upon treatment with a 1% pimecrolimus cream, rapid ing neurophysiological and neuroimmunological aspects, marked improvements were observed in the Netherton Area more has to be learned about the mediators, receptors, mul- and Severity Assessment, Eczema Area and Severity Index, tidirectional pathways in the near future to reach a valid and pruritus scores. Treatment with IFN-c has been shown golden standard for therapy. However, the complexity of to be effective not only for the improvement of erythema, interactions between the central and peripheral nervous sys- excoriations and lichenifications, but also of pruritus (164, tem and the skin in generating this symptom has catapulted 255, 256). In addition, this effect maintained up to 2 years an indeed broad but clearly delineated spectrum of molecu- after therapy (164). Amelioration of pruritus has also been lar targets into focus which, when successfully exploited, described under intravenous immunoglobulin therapy in few could serve to treat the itch perception in AD patients. cases of AD (257, 258). As of yet, however, no controlled Once these molecules will be explored systematically and in studies were performed. detail, we undoubtedly will hold sophisticated and more Also other therapeutical modalities such as TRPV1 recep- effective therapeutic strategies for pruritus management in tor antagonists/or agonists (90, 259), l-opiate receptor antag- AD in our hands. In particular, combining approaches that onists (128–130), j-opioid receptor agonists, PAR2 receptor target both the peripheral production of inflammation- antagonists, histamine-3 receptor or histamine-4 receptor tar- induced itch signals and the peripherally driven cycles that geting molecules, cannabinoid agonists, nerve-growth factor perpetuate itch and provoke spinal and central sensitization or nerve-growth factor receptor antagonists, neurokinin-1 to itch in AD are promising new strategies. The direction of receptor antagonists, GRPR antagonists, certain prostaglan- the development of innovative and more effective itch man- din and leukotriene antagonists (182–184) appear to be prom- agement is to unequivocally extend the scope of pharmaco- ising new approaches for the therapy of AD and certain logical targets far beyond the ubiquitous usual suspect allergic diseases, but will have to prove their safety and prac- histamine.

References 1. Rothman S. Physiology of itching. Physiol receptors for itch in human skin. J Neuro- 8. Handwerker HO, Schmelz M. Pain: itch Rev 1941;21:357–381. sci 1997;17:8003–8008. without pain-a labeled line for itch sensa- 2. Haniﬁn JM, Rajka G. Diagnostic features 6. Andrew D, Craig AD. Spinothalamic lam- tion? Nat Rev Neurol 2009;5:640–641. of atopic dermatitis. Acta Derm Venereol ina I neurons selectively sensitive to hista- 9. Carstens E. Responses of rat spinal dorsal Suppl (Stockh) 1980;92:44–47. mine: a central neural pathway for itch. horn neurons to intracutaneous microinjec- 3. Koblenzer CS. Itching and the atopic skin. Nat Neurosci 2001;4:72–77. tion of histamine, capsaicin, and other irri- J Allergy Clin Immunol 1999;104(3 Pt 2): 7. Paus R, Schmelz M, Biro T, Steinhoff tants. J Neurophysiol 1997;77:2499–2514. S109–S113. M. Frontiers in pruritus research: 10. Sun YG, Chen ZF. A gastrin-releasing pep- 4. von Frey M. [On the physiology of pruri- scratching the brain for more effective tide receptor mediates the itch sensation in tus]. Arch Neerland Physiol 1922;7:142–145. itch therapy. J Clin Invest 2006;116:1174– the spinal cord. Nature 2007;448:700–703. 5. Schmelz M, Schmidt R, Bickel A, Hand- 1186. 11. Carstens EE, Carstens MI, Simons CT, werker HO, Torebjork HE. Speciﬁc C- Jinks SL. Dorsal horn neurons expressing

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 815 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

NK-1 receptors mediate scratching in rats. 27. Stander S, Weisshaar E, Luger TA. Neuro- in atopic dermatitis patients. Acta Derm Neuroreport 2010;21:303–308. physiological and neurochemical basis of Venereol 1991;71:291–295. 12. Mantyh PW, Rogers SD, Honore P, Allen modern pruritus treatment. Exp Dermatol 41. Bell JK, McQueen DS, Rees JL. Involve- BJ, Ghilardi JR, Li J et al. Inhibition of 2008;17:161–169. ment of histamine H4 and H1 receptors in hyperalgesia by ablation of lamina I spinal 28. Barthel W, Markwardt F. Aggregation of scratching induced by histamine receptor neurons expressing the substance P recep- blood platelets by adrenaline and its uptake. agonists in Balb C mice. Br J Pharmacol tor. Science 1997;278:275–279. Biochem Pharmacol 1975;24:1903–1904. 2004;142:374–380. 13. Nichols ML, Allen BJ, Rogers SD, 29. Hagermark O, Strandberg K, Gronneberg 42. Roosterman D, Goerge T, Schneider SW, Ghilardi JR, Honore P, Luger NM et al. R. Effects of histamine receptor antago- Bunnett NW, Steinhoff M. Neuronal con- Transmission of chronic nociception by nists on histamine-induced responses in trol of skin function: the skin as a neuro- spinal neurons expressing the substance human skin. Acta Derm Venereol immunoendocrine organ. Physiol Rev P receptor. Science 1999;286:1558–1561. 1979;59:297–300. 2006;86:1309–1379. 14. Hsieh JC, Hagermark O, Stahle-Backdahl 30. Sugimoto Y, Iba Y, Nakamura Y, Kayasu- 43. Cowden JM, Zhang M, Dunford PJ, Thur- M, Ericson K, Eriksson L, Stone-Elander ga R, Kamei C. Pruritus-associated mond RL. The histamine H(4) receptor S et al. Urge to scratch represented in the response mediated by cutaneous histamine mediates inﬂammation and pruritus in human cerebral cortex during itch. J Neu- H3 receptors. Clin Exp Allergy Th2-dependent dermal inﬂammation. rophysiol 1994;72:3004–3008. 2004;34:456–459. J Invest Dermatol 2010;130:1023–1033. 15. Drzezga A, Darsow U, Treede RD, Siebner 31. Ruzicka T, Gluck S. Cutaneous histamine 44. Heyer G, Ulmer FJ, Schmitz J, Handwer- H, Frisch M, Munz F et al. Central activa- levels and histamine releasability from the ker HO. Histamine-induced itch and allok- tion by histamine-induced itch: analogies to skin in atopic dermatitis and hyper-IgE- nesis (itchy skin) in atopic eczema patients pain processing: a correlational analysis of syndrome. Arch Dermatol Res 1983;275: and controls. Acta Derm Venereol 1995;

O-15 H2O positron emission tomography 41–44. 75:348–352. studies. Pain 2001;92:295–305. 32. Hanifin JM. The role of antihistamines in 45. Rukwied R, Heyer G. Cutaneous reactions 16. Mochizuki H, Tashiro M, Kano M, Saku- atopic dermatitis. J Allergy Clin Immunol and sensations after intracutaneous injec- rada Y, Itoh M, Yanai K. Imaging of cen- 1990;86(4 Pt 2):666–669. tion of vasoactive intestinal polypeptide tral itch modulation in the human brain 33. Klein PA, Clark RA. An evidence-based and acetylcholine in atopic eczema patients using positron emission tomography. Pain review of the efficacy of antihistamines in and healthy controls. Arch Dermatol Res 2003;105:339–346. relieving pruritus in atopic dermatitis. Arch 1998;290:198–204. 17. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu Dermatol 1999;135:1522–1525. 46. Wahlgren CF. Pathophysiology of itching XY, Chen ZF. Cellular basis of itch sensa- 34. Munday J, Bloomfield R, Goldman M, in urticaria and atopic dermatitis. Allergy tion. Science 2009;325:1531–1534. Robey H, Kitowska GJ, Gwiezdziski Z et 1992;47(2 Pt 1):65–75. 18. Lewis T. The blood vessels of the human al. Chlorpheniramine is no more effective 47. Wahlgren CF. Measurement of itch. Semin skin and their responses. London: Shaw than placebo in relieving the symptoms of Dermatol 1995;14:277–284. and Sons, 1927. childhood atopic dermatitis with a noctur- 48. Ansel JC, Kaynard AH, Armstrong CA, 19. Lewis T, Grant RT, Marvin HM. Vascular nal itching and scratching component. Olerud J, Bunnett N, Payan D. Skin-ner- reactions of the skin to injury. Heart Dermatology 2002;205:40–45. vous system interactions. J Invest Dermatol 1929;14:139–160. 35. Rukwied R, Lischetzki G, McGlone F, 1996;106:198–204. 20. Williams DH. Skin temperature reaction to Heyer G, Schmelz M. Mast cell mediators 49. Scholzen T, Armstrong CA, Bunnett histamine in atopic dermatitis (dissemi- other than histamine induce pruritus in NW, Luger TA, Olerud JE, Ansel JC. nated neurodermatitis). J Invest Dermatol atopic dermatitis patients: a dermal micro- Neuropeptides in the skin: interactions 1938;1:119–129. dialysis study. Br J Dermatol 2000; between the neuroendocrine and the skin 21. Johnson HH, Jr, Deoreo GA, Lascheid 142:1114–1120. immune systems. Exp Dermatol WP, Mitchell F. Skin histamine levels in 36. Heyer G, Hornstein OP, Handwerker HO. 1998;7:81–96. chronic atopic dermatitis. J Invest Derma- Skin reactions and itch sensation induced 50. Slominski A, Wortsman J. Neuroendocri- tol 1960;34:237–238. by epicutaneous histamine application in nology of the skin. Endocr Rev 22. Juhlin L. Localization and content of hista- atopic dermatitis and controls. J Invest 2000;21:457–487. mine in normal and diseased skin. Acta Dermatol 1989;93:492–496. 51. Pincelli C, Fantini F, Massimi P, Giannetti Derm Venereol 1967;47:383–391. 37. Heyer G, Koppert W, Martus P, Handwer- A. Neuropeptide Y-like immunoreactivity in 23. Hill SJ. Distribution, properties, and func- ker HO. Histamine and cutaneous nocicep- Langerhans cells from patients with atopic tional characteristics of three classes of his- tion: histamine-induced responses in dermatitis. Int J Neurosci 1990;51:219–220. tamine receptor. Pharmacol Rev patients with atopic eczema, psoriasis and 52. Pincelli C, Fantini F, Massimi P, Girolo- 1990;42:45–83. urticaria. Acta Derm Venereol 1998;78:123– moni G, Seidenari S, Giannetti A. Neuro- 24. Turner AJ, Hick PE. Inhibition of alde- 126. peptides in skin from patients with atopic hyde reductase by acidic metabolites of the 38. Heyer GR, Hornstein OP. Recent studies dermatitis: an immunohistochemical study. biogenic amines. Biochem Pharmacol of cutaneous nociception in atopic and Br J Dermatol 1990;122:745–750. 1975;24:1731–1733. non-atopic subjects. J Dermatol 53. Tobin D, Nabarro G, Baart de la Faille H, 25. Malaviya R, Morrison AR, Pentland AP. 1999;26:77–86. van Vloten WA, van der Putte SC, Schuur- Histamine in human epidermal cells is 39. Uehara M. Reduced histamine reaction in man HJ. Increased number of immunore- induced by ultraviolet light injury. J Invest atopic dermatitis. Arch Dermatol active nerve fibers in atopic dermatitis. J Dermatol 1996;106:785–789. 1982;118:244–245. Allergy Clin Immunol 1992;90(4 Pt 1):613– 26. Haas HL, Sergeeva OA, Selbach O. Hista- 40. Heyer G, Hornstein OP, Handwerker HO. 622. mine in the nervous system. Physiol Rev Reactions to intradermally injected sub- 54. Anand P, Springall DR, Blank MA, Sellu 2008;88:1183–1241. stance P and topically applied mustard oil D, Polak JM, Bloom SR. Neuropeptides in

816 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases

skin disease: increased VIP in eczema and 68. Heyer G, Vogelgsang M, Hornstein OP. 83. Chuang HH, Prescott ED, Kong H, psoriasis but not axillary hyperhidrosis. Br Acetylcholine is an inducer of itching in Shields S, Jordt SE, Basbaum AI et al. J Dermatol 1991;124:547–549. patients with atopic eczema. J Dermatol Bradykinin and nerve growth factor release 55. Fantini F, Pincelli C, Romualdi P, Dona- 1997;24:621–625. the capsaicin receptor from PtdIns(4,5)P2- tini A, Giannetti A. Substance P levels are 69. Vogelsang M, Heyer G, Hornstein OP. mediated inhibition. Nature 2001;411:957– decreased in lesional skin of atopic derma- Acetylcholine induces different cutaneous 962. titis. Exp Dermatol 1992;1:127–128. sensations in atopic and non-atopic sub- 84. Hwang SW, Cho H, Kwak J, Lee SY, 56. Pincelli C, Fantini F, Romualdi P, Lesa G, jects. Acta Derm Venereol 1995;75:434–436. Kang CJ, Jung J et al. Direct activation of Giannetti A. Skin levels of vasoactive intes- 70. Ikoma A, Fartasch M, Heyer G, Miyachi capsaicin receptors by products of lipoxy- tinal polypeptide in atopic dermatitis. Arch Y, Handwerker H, Schmelz M. Painful genases: endogenous capsaicin-like sub- Dermatol Res 1991;283:230–232. stimuli evoke itch in patients with chronic stances. Proc Natl Acad Sci USA 57. Andoh T, Nagasawa T, Satoh M, Kuraishi pruritus: central sensitization for itch. 2000;97:6155–6160. Y. Substance P induction of itch-associated Neurology 2004;62:212–217. 85. Mohapatra DP, Nau C. Desensitization of response mediated by cutaneous NK1 71. Ikoma A, Rukwied R, Stander S, Steinhoff capsaicin-activated currents in the vanilloid tachykinin receptors in mice. J Pharmacol M, Miyachi Y, Schmelz M. Neuronal receptor TRPV1 is decreased by the cyclic Exp Ther 1998;286:1140–1145. sensitization for histamine-induced itch in AMP-dependent protein kinase pathway. 58. Scholzen TE, Steinhoff M, Bonaccorsi P, lesional skin of patients with atopic J Biol Chem 2003;278:50080–50090. Klein R, Amadesi S, Geppetti P et al. dermatitis. Arch Dermatol 2003;139: 86. Shin J, Cho H, Hwang SW, Jung J, Shin Neutral endopeptidase terminates substance 1455–1458. CY, Lee SY et al. Bradykinin-12-lipoxy- P-induced inflammation in allergic contact 72. Shelley WB, Arthur RP. The neurohistolo- genase-VR1 signaling pathway for inflam- dermatitis. J Immunol 2001;166:1285–1291. gy and neurophysiology of the itch sensa- matory hyperalgesia. Proc Natl Acad Sci 59. Stellwagen E, Babul J. Stabilization of the tion in man. AMA Arch Derm 1957;76: USA 2002;99:10150–10155. globular structure of ferricytochrome c by 296–323. 87. Di Marzo V, Blumberg PM, Szallasi A. chloride in acidic solvents. Biochemistry 73. Bernstein JE. Capsaicin in dermatologic Endovanilloid signaling in pain. Curr Opin 1975;14:5135–5140. disease. Semin Dermatol 1988;7:304–309. Neurobiol 2002;12:372–379. 60. Thomsen JS, Sonne M, Benfeldt E, Jensen 74. Brickford RG. Experiments relating to the 88. Caterina MJ, Julius D. The vanilloid recep- SB, Serup J, Menne T. Experimental itch itch sensation, its peripheral mechanism tor: a molecular gateway to the pain path- in sodium lauryl sulphate-inflamed and and central pathway. Clin Sci 1938;3:377– way. Annu Rev Neurosci 2001;24:487–517. normal skin in humans: a randomized, 386. 89. Caterina MJ, Schumacher MA, Tominaga double-blind, placebo-controlled study of 75. Steinhoff M, Vergnolle N, Young SH, M, Rosen TA, Levine JD, Julius D. The histamine and other inducers of itch. Br J Tognetto M, Amadesi S, Ennes HS et al. capsaicin receptor: a heat-activated ion Dermatol 2002;146:792–800. Agonists of proteinase-activated receptor channel in the pain pathway. Nature 61. Ohmura T, Hayashi T, Satoh Y, Konomi 2 induce inflammation by a neurogenic 1997;389:816–824. A, Jung B, Satoh H. Involvement of mechanism. Nat Med 2000;6:151–158. 90. Stander S, Luger T, Metze D. Treatment substance P in scratching behaviour in an 76. Steinhoff M, Neisius U, Ikoma A, of prurigo nodularis with topical capsaicin. atopic dermatitis model. Eur J Pharmacol Fartasch M, Heyer G, Skov PS et al. J Am Acad Dermatol 2001;44:471–478. 2004;491:191–194. Proteinase-activated receptor-2 mediates 91. Twycross R, Greaves MW, Handwerker H, 62. Grando SA, Kist DA, Qi M, Dahl MV. itch: a novel pathway for pruritus in Jones EA, Libretto SE, Szepietowski JC Human keratinocytes synthesize, secrete, human skin. J Neurosci 2003;23:6176– et al. Itch: scratching more than the sur- and degrade acetylcholine. J Invest Derma- 6180. face. QJM 2003;96:7–26. tol 1993;101:32–36. 77. Liu Q, Tang Z, Surdenikova L, Kim S, 92. Yosipovitch G, Greaves MW, Schmelz M 63. Grando SA, Zelickson BD, Kist DA, Patel KN, Kim A et al. Sensory neuron- Itch. Lancet 2003;361:690–694. Weinshenker D, Bigliardi PL, Wendelscha- specific GPCR Mrgprs are itch receptors 93. Stander S, Steinhoff M. Pathophysiology fer-Crabb G et al. Keratinocyte muscarinic mediating chloroquine-induced pruritus. of pruritus in atopic dermatitis: an over- acetylcholine receptors: immunolocalization Cell 2009;139:1353–1365. view. Exp Dermatol 2002;11:12–24. and partial characterization. J Invest Der- 78. Dong X, Han S, Zylka MJ, Simon MI, 94. Senba E, Katanosaka K, Yajima H, Miz- matol 1995;104:95–100. Anderson DJ. A diverse family of GPCRs umura K. The immunosuppressant FK506 64. Kurzen H, Schallreuter KU. Novel aspects expressed in specific subsets of nociceptive activates capsaicin- and bradykinin-sensi- in cutaneous biology of acetylcholine syn- sensory neurons. Cell 2001;106:619–632. tive DRG neurons and cutaneous C-fibers. thesis and acetylcholine receptors. Exp 79. Zylka MJ, Dong X, Southwell AL, Ander- Neurosci Res 2004;50:257–262. Dermatol 2004;13(Suppl. 4):27–30. son DJ. Atypical expansion in mice of the 95. Stander S, Luger TA. [Antipruritic effects 65. Miyamoto T, Nojima H, Kuraishi Y. sensory neuron-specific Mrg G protein-cou- of pimecrolimus and tacrolimus]. Hautarzt Intradermal cholinergic agonists induce pled receptor family. Proc Natl Acad Sci 2003;54:413–417. itch-associated response via M3 muscarinic USA 2003;100:10043–10048. 96. Nagy I, Santha P, Jancso G, Urban L. The acetylcholine receptors in mice. Jpn J Phar- 80. Lembo PM, Grazzini E, Groblewski T, role of the vanilloid (capsaicin) receptor macol 2002;88:351–354. O’Donnell D, Roy MO, Zhang J et al. (TRPV1) in physiology and pathology. Eur 66. Scott A. Acetylcholine in normal and dis- Proenkephalin A gene products activate a J Pharmacol 2004;500:351–369. eased skin. Br J Dermatol 1962;74:317–322. new family of sensory neuron–specific 97. Szallasi A. Small molecule vanilloid 67. Schmelz M, Schmidt R, Weidner C, Hilliges GPCRs. Nat Neurosci 2002;5:201–209. TRPV1 receptor antagonists approaching M, Torebjork HE, Handwerker HO. Chemi- 81. Bandell M, Patapoutian A. Itching for drug status: can they live up to the expec- cal response pattern of different classes of insight. Cell 2009;139:1224–1226. tations? Naunyn Schmiedebergs Arch Phar- C-nociceptors to pruritogens and algogens. 82. Clapham DE. TRP channels as cellular macol 2006;373:273–286. J Neurophysiol 2003;89:2441–2448. sensors. Nature 2003;426:517–524.

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 817 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

98. Szallasi A, Blumberg PM. Vanilloid (Cap- influx via TRPV1 channels. EMBO J and antinociception. Anesthesiology saicin) receptors and mechanisms. Pharma- 2005;24:3026–3037. 2000;92:795–805. col Rev 1999;51:159–212. 111. Dvorak M, Watkinson A, McGlone F, 124. Stein C. The control of pain in peripheral 99. Bodo E, Kovacs I, Telek A, Varga A, Paus Rukwied R. Histamine induced responses tissue by opioids. N Engl J Med R, Kovacs L et al. Vanilloid receptor-1 are attenuated by a cannabinoid receptor 1995;332:1685–1690. (VR1) is widely expressed on various agonist in human skin. Inflamm Res 125. Summerfield JA. Pain, itch and endor- epithelial and mesenchymal cell types of 2003;52:238–245. phins. Br J Dermatol 1981;105:725–726. human skin. J Invest Dermatol 112. Maccarrone M, Di Rienzo M, Battista N, 126. Bergasa NV, Alling DW, Talbot TL, Swain 2004;123:410–413. Gasperi V, Guerrieri P, Rossi A et al. The MG, Yurdaydin C, Turner ML et al. 100. Denda M, Fuziwara S, Inoue K, Denda S, endocannabinoid system in human kerati- Effects of naloxone infusions in patients Akamatsu H, Tomitaka A et al. Immuno- nocytes. Evidence that anandamide inhibits with the pruritus of cholestasis. A double- reactivity of VR1 on epidermal keratino- epidermal differentiation through CB1 blind, randomized, controlled trial. Ann cyte of human skin. Biochem Biophys Res receptor-dependent inhibition of protein Intern Med 1995;123:161–167. Commun 2001;285:1250–1252. kinase C, activation protein-1, and trans- 127. Bernstein JE, Grinzi RA. Butorphanol- 101. Inoue K, Koizumi S, Fuziwara S, Denda glutaminase. J Biol Chem 2003;278:33896– induced pruritus antagonized by naloxone. S, Inoue K, Denda M. Functional vanilloid 33903. J Am Acad Dermatol 1981;5:227–228. receptors in cultured normal human epider- 113. Stander S, Schmelz M, Metze D, Luger T, 128. Brune A, Metze D, Luger TA, Stander S. mal keratinocytes. Biochem Biophys Res Rukwied R. Distribution of cannabinoid [Antipruritic therapy with the oral opioid Commun 2002;291:124–129. receptor 1 (CB1) and 2 (CB2) on sensory receptor antagonist naltrexone. Open, non- 102. Stander S, Moormann C, Schumacher M, nerve fibers and adnexal structures in placebo controlled administration in 133 Buddenkotte J, Artuc M, Shpacovitch V et human skin. J Dermatol Sci 2005;38:177– patients]. Hautarzt 2004;55:1130–1136. al. Expression of vanilloid receptor subtype 188. 129. Metze D, Reimann S, Beissert S, Luger T. 1 in cutaneous sensory nerve fibers, mast 114. Kemeny L. Comparative study of S236 Efficacy and safety of naltrexone, an oral cells, and epithelial cells of appendage cream and hydrocortisone 1% in patients opiate receptor antagonist, in the treatment structures. Exp Dermatol 2004;13:129–139. with atopic dermatitis (Abstract). JAm of pruritus in internal and dermatological 103. Bodo E, Biro T, Telek A, Czifra G, Griger Acad Dermatol 2006;52(suppl.):68. diseases. J Am Acad Dermatol Z, Toth BI et al. A hot new twist to hair 115. Ward L, Wright E, McMahon SB. A com- 1999;41:533–539. biology: involvement of vanilloid receptor- parison of the effects of noxious and innoc- 130. Metze D, Reimann S, Luger TA. Effective 1 (VR1/TRPV1) signaling in human hair uous counterstimuli on experimentally treatment of pruritus with naltrexone, an growth control. Am J Pathol 2005;166:985– induced itch and pain. Pain 1996;64: orally active opiate antagonist. Ann NY 998. 129–138. Acad Sci 1999;885:430–432. 104. Southall MD, Li T, Gharibova LS, Pei Y, 116. Nilsson HJ, Levinsson A, Schouenborg J. 131. Penning JP, Samson B, Baxter AD. Rever- Nicol GD, Travers JB. Activation of epi- Cutaneous field stimulation (CFS): a new sal of epidural morphine-induced respira- dermal vanilloid receptor-1 induces release powerful method to combat itch. Pain tory depression and pruritus with of proinflammatory mediators in human 1997;71:49–55. nalbuphine. Can J Anaesth 1988;35: keratinocytes. J Pharmacol Exp Ther 117. Yosipovitch G, Fast K, Bernhard JD. 599–604. 2003;304:217–222. Noxious heat and scratching decrease his- 132. Summerfield JA. Naloxone modulates the 105. Pecze L, Szabo K, Szell M, Josvay K, Kas- tamine-induced itch and skin blood flow. perception of itch in man. Br J Clin Phar- zas K, Kusz E et al. Human keratinocytes J Invest Dermatol 2005;125:1268–1272. macol 1980;10:180–183. are vanilloid resistant. PLoS ONE 118. Atanassoff PG, Brull SJ, Zhang J, Green- 133. Cohen SE, Ratner EF, Kreitzman TR, 2008;3:e3419. quist K, Silverman DG, Lamotte RH. Archer JH, Mignano LR. Nalbuphine is 106. Nilius B, Owsianik G, Voets T, Peters JA. Enhancement of experimental pruritus and better than naloxone for treatment of side Transient receptor potential cation chan- mechanically evoked dysesthesiae with effects after epidural morphine. Anesth nels in disease. Physiol Rev 2007;87:165– local anesthesia. Somatosens Mot Res Analg 1992;75:747–752. 217. 1999;16:291–298. 134. Rawal N, Schott U, Dahlstrom B, Inturrisi 107. Yoshioka T, Imura K, Asakawa M, Suzuki 119. Bernstein JE, Swift R. Relief of intractable CE, Tandon B, Sjostrand U et al. Influence M, Oshima I, Hirasawa T et al. Impact of pruritus with naloxone. Arch Dermatol of naloxone infusion on analgesia and the Gly573Ser substitution in TRPV3 on 1979;115:1366–1367. respiratory depression following epidural the development of allergic and pruritic 120. Fjellner B, Hagermark O. Potentiation of morphine. Anesthesiology 1986;64: dermatitis in mice. J Invest Dermatol histamine-induced itch and flare responses 194–201. 2009;129:714–722. in human skin by the enkephalin analogue 135. Rebel A, Sloan P, Andrykowski M. Post- 108. Klein TW. Cannabinoid-based drugs as FK-33-824, beta-endorphin and morphine. operative analgesia after radical prostatec- anti-inflammatory therapeutics. Nat Rev Arch Dermatol Res 1982;274:29–37. tomy with high-dose intrathecal morphine Immunol 2005;5:400–411. 121. Fjellner B, Hagermark O. The influence of and intravenous naloxone: a retrospective 109. Akerman S, Kaube H, Goadsby PJ. the opiate antagonist naloxone on experi- review. J Opioid Manag 2009;5:331–339. Anandamide acts as a vasodilator of dural mental pruritus. Acta Derm Venereol 136. Ko MC, Husbands SM. Effects of atypical blood vessels in vivo by activating TRPV1 1984;64:73–75. kappa opioid receptor agonists on intrathe- receptors. Br J Pharmacol 2004;142:1354– 122. Hagermark O. Peripheral and central cal morphine-induced itch and analgesia in 1360. mediators of itch. Skin Pharmacol 1992; primates. J Pharmacol Exp Ther 110. van der Stelt M, Trevisani M, Vellani V, 5:1–8. 2009;328:193–200. De Petrocellis L, Schiano Moriello A, 123. Ko MC, Naughton NN. An experimental 137. Braudeau C, Bouchet D, Tesson L, Iyer S, Campi B et al. Anandamide acts as an itch model in monkeys: characterization of Remy S, Buelow R et al. Induction of intracellular messenger amplifying Ca2+ intrathecal morphine-induced scratching long-term cardiac allograft survival by

818 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases

heme oxygenase-1 gene transfer. Gene Ther tion induced by intradermally injected 162. Silver RT. A new treatment for polycythe- 2004;11:701–710. interleukin-2 in atopic dermatitis patients mia vera: recombinant interferon alfa. 138. Heishman SJ, Stitzer ML, Bigelow GE, and healthy subjects. Arch Dermatol Res Blood 1990;76:664–665. Liebson IA. Acute opioid physical depen- 1995;287:572–580. 163. Reinhold U, Kukel S, Brzoska J, Kreysel dence in postaddict humans: naloxone 150. Martin HA. Bradykinin potentiates the HW. Systemic interferon gamma treatment dose effects after brief morphine expo- chemoresponsiveness of rat cutaneous C- in severe atopic dermatitis. J Am Acad sure. J Pharmacol Exp Ther fibre polymodal nociceptors to interleukin- Dermatol 1993;29:58–63. 1989;248:127–134. 2. Arch Physiol Biochem 1996;104:229–238. 164. Stevens SR, Hanifin JM, Hamilton T, 139. Kishioka S, Paronis CA, Lewis JW, Woods 151. Sticherling M, Bornscheuer E, Schroder Tofte SJ, Cooper KD. Long-term effective- JH. Buprenorphine and methoclocinna- JM, Christophers E. Localization of neu- ness and safety of recombinant human mox: agonist and antagonist effects on trophil-activating peptide-1/interleukin-8- interferon gamma therapy for atopic der- respiratory function in rhesus monkeys. immunoreactivity in normal and psoriatic matitis despite unchanged serum IgE levels. Eur J Pharmacol 2000;391:289–297. skin. J Invest Dermatol 1991;96:26–30. Arch Dermatol 1998;134:799–804. 140. Ko MC, Lee H, Song MS, Sobczyk-Kojiro 152. Kimata H, Lindley I. Detection of plasma 165. Reinhold U, Wehrmann W, Kukel S, K, Mosberg HI, Kishioka S et al. Activa- interleukin-8 in atopic dermatitis. Arch Dis Kreysel HW. Evidence that defective inter- tion of kappa-opioid receptors inhibits Child 1994;70:119–122. feron-gamma production in atopic dermati- pruritus evoked by subcutaneous or intra- 153. Hatano Y, Katagiri K, Takayasu S. tis patients is due to intrinsic abnormalities. thecal administration of morphine in Increased levels in vivo of mRNAs for Clin Exp Immunol 1990;79:374–379. monkeys. J Pharmacol Exp Ther 2003;305: IL-8 and macrophage inflammatory pro- 166. Grewe M, Vogelsang K, Ruzicka T, Stege 173–179. tein-1 alpha (MIP-1 alpha), but not of H, Krutmann J. Neurotrophin-4 produc- 141. Wikstrom B, Gellert R, Ladefoged SD, RANTES mRNA in peripheral blood tion by human epidermal keratinocytes: Danda Y, Akai M, Ide K et al. Kappa- mononuclear cells of patients with atopic increased expression in atopic dermatitis. opioid system in uremic pruritus: multi- dermatitis (AD). Clin Exp Immunol 1999; J Invest Dermatol 2000;114:1108–1112. center, randomized, double-blind, placebo- 117:237–243. 167. Akdis CA, Akdis M, Trautmann A, Blaser controlled clinical studies. J Am Soc 154. Lippert U, Hoer A, Moller A, Ramboer I, K. Immune regulation in atopic dermatitis. Nephrol 2005;16:3742–3747. Cremer B, Henz BM. Role of antigen- Curr Opin Immunol 2000;12:641–646. 142. Georgala S, Schulpis KH, Papaconstanti- induced cytokine release in atopic pruritus. 168. Czarnetzki BM, Csato M. Comparative nou ED, Stratigos J. Raised beta-endor- Int Arch Allergy Immunol 1998;116: studies of human eosinophil migration phin serum levels in children with atopic 36–39. towards platelet-activating factor and leu- dermatitis and pruritus. J Dermatol Sci 155. Takaoka A, Arai I, Sugimoto M, Yamagu- kotriene B4. Int Arch Allergy Appl Immu- 1994;8:125–128. chi A, Tanaka M, Nakaike S. Expression nol 1989;88:191–193. 143. Bigliardi-Qi M, Lipp B, Sumanovski LT, of IL-31 gene transcripts in NC/Nga mice 169. Sigal CE, Valone FH, Holtzman MJ, Buechner SA, Bigliardi PL. Changes of epi- with atopic dermatitis. Eur J Pharmacol Goetzl EJ. Preferential human eosinophil dermal mu-opiate receptor expression and 2005;516:180–181. chemotactic activity of the platelet-activat- nerve endings in chronic atopic dermatitis. 156. Kasraie S, Niebuhr M, Werfel T. Interleu- ing factor (PAF) 1-0-hexadecyl-2-acetyl- Dermatology 2005;210:91–99. kin (IL)-31 induces pro-inflammatory cyto- sn-glyceryl-3-phosphocholine (AGEPC). 144. Biro T, Ko MC, Bromm B, Wei ET, Big- kines in human monocytes and J Clin Immunol 1987;7:179–184. liardi P, Siebenhaar F et al. How best to macrophages following stimulation with 170. Velazquez JR, Lacy P, Moqbel R. Replen- fight that nasty itch – from new insights staphylococcal exotoxins. Allergy 2009; ishment of RANTES mRNA expression in into the neuroimmunological, neuroendo- DOI: 10.1111/j.1398-9995.2009.02255.x. activated eosinophils from atopic asthmat- crine, and neurophysiological bases of pru- 157. Sonkoly E, Muller A, Lauerma AI, Piv- ics. Immunology 2000;99:591–599. ritus to novel therapeutic approaches. Exp arcsi A, Soto H, Kemeny L et al. IL-31: a 171. Weller PF, Lee CW, Foster DW, Corey Dermatol 2005;14:225–240. new link between T cells and pruritus in EJ, Austen KF, Lewis RA. Generation and 145. van Joost T, Stolz E, Heule F. Efficacy of atopic skin inflammation. J Allergy Clin metabolism of 5-lipoxygenase pathway low-dose cyclosporine in severe atopic skin Immunol 2006;117:411–417. leukotrienes by human eosinophils: pre- disease. Arch Dermatol 1987;123:166–167. 158. Bos JD, Brenninkmeijer EE, Schram ME, dominant production of leukotriene C4. 146. Wahlgren CF, Scheynius A, Hagermark O. Middelkamp-Hup MA, Spuls PI, Smitt JH. Proc Natl Acad Sci USA 1983;80: Antipruritic effect of oral cyclosporin A in Atopic eczema or atopiform dermatitis. 7626–7630. atopic dermatitis. Acta Derm Venereol Exp Dermatol 2010; DOI: 10.1111/j.1600- 172. Yamamoto J, Adachi Y, Onoue Y, Kaneg- 1990;70:323–329. 0625.2009.01024.x. ane H, Miyawaki T, Toyoda M et al. 147. Cremer B, Heimann A, Dippel E, Czar- 159. Quesada JR, Gutterman JU, Hersh EM. CD30 expression on circulating memory netzki BM. Pruritogenic effects of mitogen- Clinical and immunological study of beta CD4+ T cells as a Th2-dominated situa- stimulated peripheral blood mononuclear interferon by intramuscular route in tion in patients with atopic dermatitis. cells in atopic eczema. Acta Derm Venereol patients with metastatic breast cancer. Allergy 2000;55:1011–1018. 1995;75:426–428. J Interferon Res 1982;2:593–599. 173. Lebel B, Venencie PY, Saurat JH, Sou- 148. Darsow U, Scharein E, Bromm B, Ring J. 160. de Wolf JT, Hendriks DW, Egger RC, brane C, Paupe J. Anti-IgE induced hista- Skin testing of the pruritogenic activity of Esselink MT, Halie MR, Vellenga E. mine release from basophils in children histamine and cytokines (interleukin-2 and Alpha-interferon for intractable pruritus in with atopic dermatitis. Acta Derm Venereol tumour necrosis factor-alpha) at the der- polycythaemia vera. Lancet 1991;337:241. Suppl (Stockh) 1980;92:57–59. mal–epidermal junction. Br J Dermatol 161. Kolde G, Sunderkotter C, Luger TA. 174. von der Helm D, Ring J, Dorsch W. Com- 1997;137:415–417. Treatment of urticaria pigmentosa using parison of histamine release and prosta- 149. Wahlgren CF, Tengvall Linder M, Hager- interferon alpha. Br J Dermatol glandin E2 production of human basophils mark O, Scheynius A. Itch and inflamma- 1995;133:91–94.

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 819 Pruritus in allergic and atopic diseases Buddenkotte and Steinhoff

in atopic and normal individuals. Arch dermatitis. Measurement with the Corne- 204. Arnetz BB, Fjellner B, Eneroth P, Kallner Dermatol Res 1987;279:536–542. ometer CM 420. Acta Derm Venereol A. Endocrine and dermatological concom- 175. Bull HA, Courtney PF, Bunker CB, Rustin 1986;66:281–284. itants of mental stress. Acta Derm Venereol MH, Pearce FL, Dowd PM. Basophil 190. Fartasch M, Diepgen TL. The barrier Suppl (Stockh) 1991;156:9–12. mediator release in atopic dermatitis. J function in atopic dry skin. Disturbance 205. Buhk H, Muthny FA. [Psychophysiologic Invest Dermatol 1993;100:305–309. of membrane-coating granule exocytosis and psychoneuroimmunologic studies in 176. Jarvikallio A, Naukkarinen A, Harvima and formation of epidermal lipids? Acta neurodermatitis. Overview and critical eval- IT, Aalto ML, Horsmanheimo M. Quanti- Derm Venereol Suppl (Stockh) 1992;176: uation]. Hautarzt 1997;48:5–11. tative analysis of tryptase- and chymase- 26–31. 206. Hermanns N, Scholz OB. Kognitive containing mast cells in atopic dermatitis 191. Werner Y, Lindberg M, Forslind B. Einflu¨sse auf einen histamininduzierten and nummular eczema. Br J Dermatol Membrane-coating granules in ‘‘dry’’ non- Juckreiz und Quaddelbildung bei der 1997;136:871–877. eczematous skin of patients with atopic atopischen Dermatitis. Verhaltensmod 177. Fjellner B, Hagermark O. Experimental dermatitis. A quantitative electron micro- Verhaltensmed 1992;13:171–194. pruritus evoked by platelet activating fac- scopic study. Acta Derm Venereol 207. Ehlers A, Stangier U, Gieler U. Treatment tor (PAF-acether) in human skin. Acta 1987;67:385–390. of atopic dermatitis: a comparison of psy- Derm Venereol 1985;65:409–412. 192. Ha¨germark O¨. The pathophysiology of chological and dermatological approaches 178. Abeck D, Andersson T, Grosshans E, itch. In: Ruzicka T, Przybilla B, Ring J, to relapse prevention. J Consult Clin Psy- Jablonska S, Kragballe K, Vahlquist A editors. Handbook of atopic eczema. chol 1995;63:624–635. et al. Topical application of a platelet- Berlin: Springer, 1991:278–286. 208. Shenefelt PD. Hypnosis in dermatology. activating factor (PAF) antagonist in 193. Wahlgren CF. Itch and atopic dermatitis: Arch Dermatol 2000;136:393–399. atopic dermatitis. Acta Derm Venereol an overview. J Dermatol 1999;26:770–779. 209. Singh LK, Pang X, Alexacos N, Letour- 1997;77: 449–451. 194. Yoshiike T, Aikawa Y, Sindhvananda J, neau R, Theoharides TC. Acute immobili- 179. Devillier P, Baccard N, Advenier C. Leu- Suto H, Nishimura K, Kawamoto T et al. zation stress triggers skin mast cell kotrienes, leukotriene receptor antagonists Skin barrier defect in atopic dermatitis: degranulation via corticotropin releasing and leukotriene synthesis inhibitors in increased permeability of the stratum cor- hormone, neurotensin, and substance P: a asthma: an update. Part I: synthesis, recep- neum using dimethyl sulfoxide and theoph- link to neurogenic skin disorders. Brain tors and role of leukotrienes in asthma. ylline. J Dermatol Sci 1993;5:92–96. Behav Immun 1999;13:225–239. Pharmacol Res 1999;40:3–13. 195. Choi EH, Brown BE, Crumrine D, Chang 210. Buske-Kirschbaum A, Gierens A, Hollig 180. Andoh T, Kuraishi Y. Intradermal leuko- S, Man MQ, Elias PM et al. Mechanisms H, Hellhammer DH. Stress-induced immu- triene B4, but not prostaglandin E2, by which psychologic stress alters cutane- nomodulation is altered in patients with induces itch-associated responses in mice. ous permeability barrier homeostasis and atopic dermatitis. J Neuroimmunol Eur J Pharmacol 1998;353:93–96. stratum corneum integrity. J Invest Derma- 2002;129:161–167. 181. Miyoshi M, Sakurai T, Kodama S. [Clini- tol 2005;124:587–595. 211. Munzel K, Schandry R. [Atopic eczema: cal evaluation of urinary leukotriene E4 196. Griesemer RD. Emotionally triggered dis- psychophysiological reactivity with stan- levels in children with atopic dermatitis]. ease in a dermatological practice. Psychatr dardized stressors]. Hautarzt 1990;41:606– Arerugi 1999;48:1148–1152. Ann 1978;8:49–56. 611. 182. Carucci JA, Washenik K, Weinstein A, 197. Niemeier V, Kupfer J, Gieler U. Observa- 212. Beltrani VS. The clinical spectrum of ato- Shupack J, Cohen DE. The leukotriene tions during an itch-inducing lecture. pic dermatitis. J Allergy Clin Immunol antagonist zafirlukast as a therapeutic Dermatol Psychosom 2000;1:15–18. 1999;104(3 Pt 2):S87–S98. agent for atopic dermatitis. Arch Dermatol 198. Fjellner B, Arnetz BB. Psychological pre- 213. Hanifin JM. Basic and clinical aspects of 1998;134:785–786. dictors of pruritus during mental stress. atopic dermatitis. Ann Allergy 1984;52:386– 183. Woodmansee DP, Simon RA. A pilot Acta Derm Venereol 1985;65:504–508. 395. study examining the role of zileuton in ato- 199. Fjellner B, Arnetz BB, Eneroth P, Kallner 214. Rovensky J, Saxl O. Differences in the pic dermatitis. Ann Allergy Asthma Immu- A. Pruritus during standardized mental dynamics of sweat secretion in atopic chil- nol 1999;83(6 Pt 1):548–552. stress. Relationship to psychoneuroendo- dren. J Invest Dermatol 1964;43:171–176. 184. Zabawski EJ, Jr, Kahn MA, Gregg LJ. crine and metabolic parameters. Acta Derm 215. Metze D, Luger T. Nervous system in the Treatment of atopic dermatitis with Venereol 1985;65:199–205. skin. In: Freinkel RK, Woodley DT, edi- zafirlukast. Dermatol Online J 1999;5:10. 200. Metze D, Reimann S, Luger T. Juckreiz - tors. The biology of the skin. New York: 185. Hanifin JM. Pharmacophysiology of atopic Symptom oder Krankheit. In: Plewig G, Parthenon, 2001:153–176. dermatitis. Clin Rev Allergy 1986;4:43–65. Przybilla B, editors. Fortschritte der prak- 216. Graham DT, Wolf S. The relation of 186. Morren MA, Przybilla B, Bamelis M, tischen Dermatologie und Venerologie. eczema to attitude and to vascular reac- Heykants B, Reynaers A, Degreef H. Ato- Berlin: Springer, 1997:77–86. tions of the human skin. J Lab Clin Med pic dermatitis: triggering factors. JAm 201. Koblenzer CS. Psychocutaneous disease. 1953;42:238–254. Acad Dermatol 1994;31(3 Pt 1):467–473. Orlando: Grune & Stratton, 1987. 217. Bendsoe N, Bjornberg A, Asnes H. Itching 187. Rajka G. Essential aspects of atopic 202. Gupta MA, Gupta AK, Schork NJ, Ellis from wool fibres in atopic dermatitis. Con- dermatitis. Berlin: Springer, 1989. CN. Depression modulates pruritus percep- tact Dermatitis 1987;17:21–22. 188. Mihara K, Kuratani K, Matsui T, tion: a study of pruritus in psoriasis, atopic 218. Wahlgren CF, Hagermark O, Bergstrom Nakamura M, Yokota K. Vital role of the dermatitis, and chronic idiopathic urticaria. R. Patients’ perception of itch induced by itch-scratch response in development of Psychosom Med 1994;56:36–40. histamine, compound 48/80 and wool spontaneous dermatitis in NC/Nga mice. 203. Cormia FE. Experimental histamine pruri- fibres in atopic dermatitis. Acta Derm Br J Dermatol 2004;151:335–345. tus. I. Influence of physical and psychologi- Venereol 1991;71:488–494. 189. Werner Y. The water content of the stra- cal factors on threshold reactivity. J Invest 219. Ekblom A, Fjellner B, Hansson P. The tum corneum in patients with atopic Dermatol 1952;19:21–34. influence of mechanical vibratory stimula-

820 Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S Buddenkotte and Steinhoff Pruritus in allergic and atopic diseases

tion and transcutaneous electrical nerve 235. Doherty V, Sylvester DG, Kennedy CT, associated with atopic dermatitis using a stimulation on experimental pruritus Harvey SG, Calthrop JG, Gibson JR. combination of narrowband ultraviolet B induced by histamine. Acta Physiol Scand Treatment of itching in atopic eczema with phototherapy, topical corticosteroids and 1984;122:361–367. antihistamines with a low sedative profile. an antihistamine. Clin Exp Dermatol 220. Fisher AA. Nonallergic ‘‘itch’’ and BMJ 1989;298:96. 2009;34:e833–e836. ‘‘prickly’’ sensation to wool fibers in atopic 236. Hannuksela M, Kalimo K, Lammintausta 249. De Rie MA, Meinardi MM, Bos JD. and nonatopic persons. Cutis 1996;58:323– K, Mattila T, Turjanmaa K, Varjonen E et Lack of efficacy of topical cyclosporin A 324. al. Dose ranging study: cetirizine in the in atopic dermatitis and allergic contact 221. Hogan DJ, Dannaker CJ, Maibach HI. treatment of atopic dermatitis in adults. dermatitis. Acta Derm Venereol 1991; Contact dermatitis: prognosis, risk factors, Ann Allergy 1993;70:127–133. 71:452–454. and rehabilitation. Semin Dermatol 237. Danarti R, Waskito F, Indrastuti N. Onset 250. Alomar A, Berth-Jones J, Bos JD, Gian- 1990;9:233–246. and duration of action of topical antihista- netti A, Reitamo S, Ruzicka T et al. The 222. Sicherer SH, Sampson HA. Food hyper- mine: a study of histamine skin test role of topical calcineurin inhibitors in sensitivity and atopic dermatitis: patho- response. Int J Dermatol 2008;47:861–863. atopic dermatitis. Br J Dermatol physiology, epidemiology, diagnosis, and 238. Drake LA, Millikan LE. The antipruritic 2004;151(Suppl. 70):3–27. management. J Allergy Clin Immunol effect of 5% doxepin cream in patients with 251. Ashcroft DM, Dimmock P, Garside R, 1999;104(3 Pt 2):S114–S122. eczematous dermatitis. Doxepin Study Stein K, Williams HC. Efficacy and tolera- 223. Bueller HA, Bernhard JD. Review of pruri- Group. Arch Dermatol 1995;131:1403–1408. bility of topical pimecrolimus and tacroli- tus therapy. Dermatol Nurs 1998;10:101– 239. Sabroe RA, Kennedy CT, Archer CB. The mus in the treatment of atopic dermatitis: 107. effects of topical doxepin on responses to meta-analysis of randomised controlled 224. Simpson EL. Atopic dermatitis: a review of histamine, substance P and prostaglandin trials. BMJ 2005;330:516. topical treatment options. Curr Med Res E2 in human skin. Br J Dermatol 252. Novak N, Kwiek B, Bieber T. The mode Opin 2010;26:633–640. 1997;137:386–390. of topical immunomodulators in the immu- 225. Bikowski J. Case studies assessing a new 240. Shelley WB, Shelley ED, Talanin NY. nological network of atopic dermatitis. Clin skin barrier repair cream for the treatment Self-potentiating allergic contact dermatitis Exp Dermatol 2005;30:160–164. of atopic dermatitis. J Drugs Dermatol caused by doxepin hydrochloride cream. 253. Ruer-Mulard M, Aberer W, Gunstone A, 2009;8:1037–1041. J Am Acad Dermatol 1996;34:143–144. Kekki OM, Lopez Estebaranz JL, Vert- 226. Sugarman JL, Parish LC. Efficacy of a 241. Hanifin JM, Ling MR, Langley R, Bren- ruyen A et al. Twice-daily versus once- lipid-based barrier repair formulation in eman D, Rafal E. Tacrolimus ointment for daily applications of pimecrolimus cream moderate-to-severe pediatric atopic derma- the treatment of atopic dermatitis in adult 1% for the prevention of disease relapse in titis. J Drugs Dermatol 2009;8:1106–1111. patients: part I, efficacy. J Am Acad Der- pediatric patients with atopic dermatitis. 227. Vieluf D, Matthias C. Trockene juckende matol 2001;44(Suppl. 1):S28–S38. Pediatr Dermatol 2009;26:551–558. Haut – ihre Behandlung mit einer neuen 242. Jekler J, Larko O. Combined UVA-UVB 254. Yan AC, Honig PJ, Ming ME, Weber J, Polidocanol-Harnstoff-Zubereitung. Z versus UVB phototherapy for atopic der- Shah KN. The safety and efficacy of pime- Hautkr 1992;67:816–821. matitis: a paired-comparison study. JAm crolimus, 1%, cream for the treatment of 228. Lundeberg T, Bondesson L, Thomas M. Acad Dermatol 1990;22:49–53. Netherton syndrome: results from an Effect of acupuncture on experimentally 243. Luger T, Van Leent EJ, Graeber M, exploratory study. Arch Dermatol induced itch. Br J Dermatol 1987;117:771– Hedgecock S, Thurston M, Kandra A 2010;146:57–62. 777. et al. SDZ ASM 981: an emerging safe and 255. Hanifin JM, Schneider LC, Leung DY, 229. van der Schaar WW, Lamberts H. effective treatment for atopic dermatitis. Ellis CN, Jaffe HS, Izu AE et al. Recombi- [Scratching for the itch in eczema; a psy- Br J Dermatol 2001;144:788–794. nant interferon gamma therapy for atopic chodermatologic approach]. Ned Tijdschr 244. Hoare C, Li Wan Po A, Williams H. dermatitis. J Am Acad Dermatol 1993; Geneeskd 1997;141:2049–2051. Systematic review of treatments for atopic 28(2 Pt 1):189–197. 230. Melin L, Frederiksen T, Noren P, Swebi- eczema. Health Technol Assess 2000;4:1– 256. Jang IG, Yang JK, Lee HJ, Yi JY, Kim lius BG. Behavioural treatment of scratch- 191. HO, Kim CW et al. Clinical improvement ing in patients with atopic dermatitis. Br J 245. Aliaga A, Rodriguez M, Armijo M, Bravo and immunohistochemical findings in Dermatol 1986;115:467–474. J, Avila AL, Mascaro JM et al. Double- severe atopic dermatitis treated with inter- 231. Hornstein OP, Gall K, Salzer B, Ruppr- blind study of prednicarbate versus fluo- feron gamma. J Am Acad Dermatol echt M. Controlled physical exercise in cortin butyl ester in atopic dermatitis. Int J 2000;42:1033–1040. patients with chronic neurodermitis. Dtsch Dermatol 1996;35:131–132. 257. Gelfand EW, Landwehr LP, Esterl B, Z Sportmed 1998;49:39–45. 246. Maloney JM, Morman MR, Stewart DM, Mazer B. Intravenous immune globulin: an 232. Berth-Jones J, Graham-Brown RA. Failure Tharp MD, Brown JJ, Rajagopalan R. alternative therapy in steroid-dependent of terfenadine in relieving the pruritus of Clobetasol propionate emollient 0.05% in allergic diseases. Clin Exp Immunol atopic dermatitis. Br J Dermatol the treatment of atopic dermatitis. Int J 1996;104(Suppl. 1):61–66. 1989;121:635–637. Dermatol 1998;37:142–144. 258. Kimata H. High dose gammaglobulin 233. Henz BM, Metzenauer P, O’Keefe E, Zu- 247. Yosipovitch G, Szolar C, Hui XY, Mai- treatment for atopic dermatitis. Arch Dis berbier T. Differential effects of new-gener- bach H. High-potency topical corticoste- Child 1994;70:335–336. ation H1-receptor antagonists in pruritic roid rapidly decreases histamine-induced 259. Reimann S, Luger T, Metze D. [Topical dermatoses. Allergy 1998;53:180–183. itch but not thermal sensation and pain in administration of capsaicin in dermatology 234. Wahlgren CF, Hagermark O, Bergstrom human beings. J Am Acad Dermatol for treatment of itching and pain]. Hau- R. The antipruritic effect of a sedative and 1996;35:118–120. tarzt 2000;51:164–172. a non-sedative antihistamine in atopic der- 248. Oiso N, Yudate T, Kawara S, Kawada A. 260. Damann N, Voets T, Nilius B. TRPs in matitis. Br J Dermatol 1990;122:545–551. Successful treatment of lichen amyloidosus our senses. Curr Biol 2008;18:R880–R889.

Allergy 65 (2010) 805–821 ª 2010 John Wiley & Sons A/S 821